1. Sampling according to WHO guidelines
2-6
Sampling according to WHO guidelines
for sampling of pharmaceutical products
and related materials
Marta Miquel
Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, September 2009

2. WHO sampling guideline - Introduction
This guideline is primarily addressed to governmental organizations such as drug regulatory authorities (including inspectorates), quality control laboratories, customs and police officials, when surveying the national markets for the quality of drug products.
The guideline is available on the internet as Annex 4 of the WHO Technical Report Series No. 929 (2005), issued by the WHO Expert Committee on Specifications for Pharmaceutical Preparations.

3. Before sampling purpose of sampling?
type of tests intended to be applied to the samples?
type of products/materials to be sampled?
are sampling facilities adequate?
are responsibilities of the samplers clear?
Note: these topics are dealt with in the presentation
“Organisation of sampling programmes – background information”

4. Sampling process Preparation for sampling Sampling operation
Sample storage and retention

5. I - Preparation for sampling
Sampling tools should be available to the sampler, e.g. to open containers (knives, hammers,...), material to reclose the packages (sealing tape), self-adhesive labels to indicate that some of the contents have been removed, etc...
Sampling tools should be made of inert materials (e.g. polypropylene or stainless steel; avoid glass) and kept very clean. After use, thoroughly washed, rinsed with water or suitable solvent, dried and stored in clean conditions.
Disposable sampling materials can also be used.
Washing facilities should be located in, or close to, the sampling area.
Cleaning procedure should be documented and validated (= demonstrated efficiency).
Sterile pharmaceutical products should be sampled under aseptic conditions.

6. Examples of types of sampling tools (Appendix 1 of WHO guideline)
Dip tubes
for liquids
Spatulas
for solids
Sample thieves
for solid samples in deep containers
Bag-sampling spears for taking samples from bags

7. II - Sampling operation
Written sampling procedure: operations to be performed on a defined material for a specific purpose, including health/safety aspects (see Appendix 3 of WHO guideline: Examples of steps to be considered for inclusion in a SOP).
Sampling plan: description of the location, number of units and/or quantity of material that should be collected, and associated acceptance criteria.
Make sure that representative samples are taken in sufficient quantity. Representative sample: sample obtained according to a sampling procedure designed to ensure that the different parts of a batch or the different properties of a non-uniform material are proportionately represented.
Samples should never be returned to the bulk.

8. II - Sampling operation (cont.)
Sampling operations should be supervised and documented => sample collection form => always kept together with the collected sample.
Sample collection form: written record of the sampling operations, containing: batch number, sampling date/place, reference to sampling protocol used, description of containers and materials sampled, possible abnormalities, any relevant observations, name/signature of the sampler...
Store the sample in a properly labelled container: sample type, name of material, identification code, batch number, code, quantity, date of sampling, storage conditions, handling precautions, container number....

9. Example of sample collection form (Appendix 2 of WHO guideline)
Page 2
Page 1

10. II - Sampling operation (cont.)
Pay attention to any signs of non-uniformity of the material:
Differences in shape, size, colour of particles in crystalline/granular/powdered subst.
Moist crusts on hygroscopic substances.
Solid deposits in liquids or semi-liquids.
Stratification of liquids.
In this case, sample portions of the material and test them separately from the material with normal aspect.
Take into account previous experience with the product and supplier.

11. III – Sample storage and retention
Containers
Containers used to store a sample should comply with the storage directions for the active pharmaceutical ingredient, excipient or drug product:
should not interact with the sampled material.
should not allow contamination.
should protect the sample from light, air and moisture.
should be sealed and adequately labelled.
avoid mix-up when containers are opened (screw caps, separate lids).
manipulations/unauthorised opening should be easy detectable.
transported in such way as to avoid breakage.

12. III – Sample storage and retention (cont.)
Rooms for sample storage
Security and adequate storage conditions (light, ventilation, safety requirements, and any special requirements) should be ensured for the rooms in which samples are stored.
Samples should be stored according to the storage conditions as specified for the respective API, excipient or drug product.
Packaging materials similar to those in which the bulk is supplied should be used for long-term storage.

13. Bag for storage of samples
Examples of types of containers used to store samples of starting materials and bulk products (Appendix 4 of WHO guideline)
Bag for storage of samples
Screw-top containers

14. Sampling for regulatory issues
Drug quality surveillance programmes
Inspections

15. I - Drug quality surveillance programmes
The extent of the routine surveillance programmes for drug quality, carried out by National Drug Regulatory Authorities will depend on:
capacity of the national drug QC lab
extent to which the quality of the product has been assessed prior to registration
extent to which the requirements for GMP are implemented
number of products imported from abroad
The programme should include marketed products, whether registered for sale or prepared in pharmacies.
Each product should be assessed regularly (every 2-3 years).
Particular attention to products of prime importance to public health programmes or potentially dangerous, unstable or difficult to formulate properly.

16. I - Drug quality surveillance programmes (cont.)
The responsible laboratory should prepare the sampling programme (if needed under the guidance of the drug regulatory authority) every year or half a year.
Sampling programme:
Lists the products to be sampled during a given period
Specifies the sampling procedure
Specifies the size of the samples to be collected (including retention sample)
States to what extent each brand of a given product will be sampled
States which local authority or inspector will be responsible for sampling
Indicates to which laboratory each sample should be sent (if more than 1)

17. II - Inspections Inspectors may take samples from:
retail or hospital pharmacies (including preparations manufactured in bulk in the premises)
industry
wholesalers
In case of a complaint received about a product, the sample should include the original container and if possible 1 or 2 unopened containers with the same batch number.
In case of deteriorated dosage forms, the sample should consist of one or more containers showing visual signs of deterioration.

18. Sampling for acceptance
Starting materials
Intermediates in manufacturing and bulk products
Finished products
Packaging materials

19. I – Sampling of starting materials
Uniform material: sample can be taken from any part.
Non-uniform material:
Special sampling tools are needed.
Alternatively, if applicable, restore uniformity before sampling (e.g. stratified liquid may be stirred or a solid deposit in a liquid may be dissolved by gently warming and stirring) – validated method !
In these cases, in order to prepare representative samples, see ISO 2859.
Partially processed natural products (animal, herbal and mineral) should be treated as intrinsically non-uniform. For info, sampling of herbal drugs, see European Pharmacopoeia chapter

20. II - Sampling of intermediates in manufacturing and bulk products
Intermediates: liquids and semi-solid products; powdered solids or granulates; unit dosages forms in bulk (tablets, capsules).
Pay attention to the segregation of bulk materials during transportation.
These products may be assumed as uniform if the transportation process has been validated, AND:
They are labelled with name of the manufacturer and a single batch number;
They have been produced according to GMP; and
They are supplied with a certificate, issued in the country of origin, according to the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce

21. On this website you can find information about:
WHO Certification Scheme for Products moving in International Commerce is an international voluntary agreement, created to enable countries with limited drug regulatory capacity to obtain partial assurance from exporting countries concerning the safety, quality and efficacy of the products they plan to import.
On this website you can find information about:
competent authorities participating in this certification scheme.
model certificate of a pharmaceutical product.
guidelines on the implementation of this certification scheme.

22. III - Sampling of finished products
Uniformity : a single consignment* of a product from a single manufacturer and labelled with a single batch number may be assumed to be uniform.
The minimum size of the samples to be taken is determined by the requirements of the analytical procedure used to test the product (tests of unit dosage forms for uniformity of weight, volume or content, or sterility tests can require a large number of samples).
Sampling and testing may be adjusted according to the experience with the source of the product, e.g. manufacturer or supplier.
*Consignment: quantity of a bulk starting material or drug product, made by one manufacturer or supplied by one agent, supplied at one time in response to a particular request (1 or more containers, 1 or more batches).

23. IV - Sampling of packaging materials
Pay attention to mixing up printed packaging materials during sampling
only 1 material should be handled at a time.
adequately protect and identify the sample.
Samples of packaging materials should never be returned to the consignment.
During sampling, primary packaging materials should be protected against environmental contamination (e.g. special measures when sampling parenteral ampoules).

24. IV - Sampling of packaging materials (cont.)
A consignment of packaging materials may NOT be considered homogeneous if:
Materials manufactured on different days or machines
Materials manufactured on one machine, but different stations (e.g. printing stations, moulding stations)
Packaging manufactured with different source materials
Change in quality during the process (colour variation, text legibility or change of printing plate, container-wall thickness...)
Important to take random samples from across the consignment.
Consider focus sampling based on the abovementioned risk factors.

25. The following plans are examples
Sampling plans
Starting materials
Finished products
Packaging materials
Note: guideline primarily addressed to Drug Regulatory Authorities, these sampling plans might not be appropriate for manufacturers.
The following plans are examples

26. Sampling plans for starting materials
“n-plan”
“p-plan”
“r-plan”
See examples of use of sampling plans in Appendix 5 of WHO guideline

27. I – The “n-plan”
Only used when material is considered uniform and from a recognised source.
N = sampling units in the consignment (e.g. individual package, drum or container)
Calculate “n” (n = units to be sampled).
Select at random “n” units from N.
Take a sample from these units.
QC lab checks appearance + identity of each sample.
If results concordant => combine samples into a single final sample.
Take “analytical sample” for full testing.
Keep the rest as “retention sample”.
e.g. N=40 => n=7 (units to be sampled)

28. NOTES:
The “n-plan” is NOT statistically based and should be used only as a guiding principle.
The “n-plan” is NOT recommended for use by control laboratories of manufacturers that are required to analyse and release or reject each received consignment of the starting materials used to produce a drug product.

29. II – The “p-plan”
May be used when material is considered uniform, from a recognised source and the main purpose is to test for identity.
N = sampling units in the consignment (e.g. individual package, drum or container)
Sample each of the N sampling units.
QC lab checks appearance + identity of each sample.
If results concordant => p final samples are formed by appropriate pooling.
Keep the p samples for retention (or full testing if required).
e.g. N=40 => p=3 (final samples after testing+pooling)

30. III – The “r-plan”
May be used when material is considered non-uniform and/or obtained from a not well know source.
Can be used for herbal medicinal products used as starting materials.
N = sampling units in the consignment (e.g. individual package, drum or container)
Sample each of the N sampling units.
QC lab checks appearance + identity of each sample.
If results concordant => r samples are randomly selected.
r samples individually fully tested.
If results concordant => combine the r samples for the retention sample.
e.g. N=40 => r=10 (randomly selected samples for testing)

31. Sampling plans for packaging materials
Should be based on defined sampling standards such as:
ISO 2859
British Standard BS
ANSI/ASQ Z (American National Standards Institute/American Society for Quality)

32. Sampling plans for finished products
Should be based on defined sampling standards such as :
ISO 2859
British Standard BS
ANSI/ASQ Z (American National Standards Institute/American Society for Quality)
In some cases a visual inspection might be sufficient.
However, if physical and chemical testing is required, the sampling units should consist of whole packs (individual packs should not be broken open).

33. ISO 2859 series - Sampling procedures for inspection by attributes
ISO : Part 1: Sampling schemes indexed by acceptance quality limit (AQL) for lot-by-lot inspection
ISO : Part 2: Sampling plans indexed by limiting quality (LQ) for isolated lot inspection
ISO Part 3: Skip-lot sampling procedures
ISO : Part 4: Procedures for assessment of declared quality levels
ISO : Part 5: System of sequential sampling plans indexed by acceptance quality limit (AQL) for lot-by-lot inspection

34. Practical example
Sampling documentation used in the Austrian Food and Drug Agency “AGES” (Vienna, Austria

35. Step 1: Sampling order from a scientific advisor
Step 2: Verification and authorization of order
Step 3: Assignment to authorized sampling staff
1: ordering department
2: date / name of scientific advisor
3: urgent / planned beginning of analysis
4: requested sampling site
5: on site sampling necessary
6: specific information for transport/storage
7: name of sample
8: MA-number
9: batch number
10: quantity
11: unit
12: signature of head of dep. 1 4 2 5 3 6 7 8 9 10 11 12

36. Step 4: Sampling request sent by fax

37. … sampling performed onsite
Part 1
1: sample (name, strength, dosage form)
2: number of packages, units, quantity of samples
3: batch number
4: expiry date
5: MA-number
6: manufacturing date
7: place of withdrawal (company, wholesaler, pharmacy, others)
8: sampling by: company; official expert; official inspector; public health officer 1 2 3 5 4 6 7 8

38. Part 2 1: found storage conditions 2: light protection 3: temperature
4: cause for suspicion
5: prohibition of sale
6: crosscheck
7: sealing executed
8: certificate of analysis
9: composition/formulation
10: date of withdrawal/signature 1 2 3 4 5 6 7 8 9 10

39. Step 5: Arrival of sample
1: general information: name, MA-number, date of receipt,…
2: receipt control - temperature
3: storage conditions
4: sample damaged (yes/no) 1 2 3 4

40. References
WHO guidelines for sampling of pharmaceutical products and related materials. Annex 4 of WHO Technical Report Series No. 929 (2005).
ISO Sampling procedures for inspection by attributes.
British Standard BS Sampling procedures for inspection by attributes.
ISO 10725: Acceptance sampling plans and procedures for the inspection of bulk materials.
Good Manufacturing Practices; Part I - Basic Requirements for Medicinal Products ; Part II - Basic Requirements for Active Substances used as Starting Materials.
European Pharmacopoeia. Chapter Herbal drugs: sampling and sample preparation.
ANSI/ASQ Z Standard (American National Standards Institute/American Society for Quality) - Sampling Procedures and Tables for Inspection by Attributes.

41. Thank you for your attention
Thank you for your attention
Marta Miquel
Scientific Officer
Council of Europe
European Directorate for the Quality of Medicines and HealthCare (EDQM)
Biological Standardisation, OMCL Network & HealthCare Department (DBO)
7 Allée Kastner, CS 30026
F Strasbourg, France
Tel.: + 33 (0)
Fax: + 33 (0)